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Transcriptional mechanisms of drug addiction.

Nestler EJ - Clin Psychopharmacol Neurosci (2012)

Bottom Line: Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state.Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction.As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype.

View Article: PubMed Central - PubMed

Affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, USA.

ABSTRACT
Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state. Numerous transcription factors, proteins that bind to regulatory regions of specific genes and thereby control levels of their expression, have been implicated in the addiction process over the past decade or two. Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction. As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype. Current efforts are geared toward understanding the range of target genes through which these transcription factors produce their functional effects and the underlying molecular mechanisms involved. This work promises to reveal fundamentally new insight into the molecular basis of addiction, which will contribute to improved diagnostic tests and therapeutics for addictive disorders.

No MeSH data available.


Related in: MedlinePlus

Transcriptional actions of drugs of abuse. Although drugs of abuse act initially on their immediate protein targets at the synapse, their long-term functional effects are mediated in part via regulation of downstream signaling pathways which convertge on the cell nucleus. Here, drug regulation of transfactors leads to the stable regulation of specific target genes and to the lasting behavioral abnormalities that characterize addiction.
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Figure 1: Transcriptional actions of drugs of abuse. Although drugs of abuse act initially on their immediate protein targets at the synapse, their long-term functional effects are mediated in part via regulation of downstream signaling pathways which convertge on the cell nucleus. Here, drug regulation of transfactors leads to the stable regulation of specific target genes and to the lasting behavioral abnormalities that characterize addiction.

Mentions: Work over the past ~15 years has provided increasing evidence for a role of gene expression in drug addiction, as several transcription factors - proteins that bind to specific responses elements in the promoter regions of target genes and regulate those genes' expression - have been implicated in drug action. According to this scheme, shown in Fig. 1, drugs of abuse, via their initial actions at the synapse, produce changes within neurons that signal to the nucleus and regulate the activity of numerous transcription factors and many other types of transcriptional regulatory proteins.3) A These nuclear changes gradually and progressively build with repeated drug exposure and underlie stable changes in the expression of specific target genes which, in turn, contribute to the lasting changes in neural function that maintain a state of addiction.1,4)


Transcriptional mechanisms of drug addiction.

Nestler EJ - Clin Psychopharmacol Neurosci (2012)

Transcriptional actions of drugs of abuse. Although drugs of abuse act initially on their immediate protein targets at the synapse, their long-term functional effects are mediated in part via regulation of downstream signaling pathways which convertge on the cell nucleus. Here, drug regulation of transfactors leads to the stable regulation of specific target genes and to the lasting behavioral abnormalities that characterize addiction.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569166&req=5

Figure 1: Transcriptional actions of drugs of abuse. Although drugs of abuse act initially on their immediate protein targets at the synapse, their long-term functional effects are mediated in part via regulation of downstream signaling pathways which convertge on the cell nucleus. Here, drug regulation of transfactors leads to the stable regulation of specific target genes and to the lasting behavioral abnormalities that characterize addiction.
Mentions: Work over the past ~15 years has provided increasing evidence for a role of gene expression in drug addiction, as several transcription factors - proteins that bind to specific responses elements in the promoter regions of target genes and regulate those genes' expression - have been implicated in drug action. According to this scheme, shown in Fig. 1, drugs of abuse, via their initial actions at the synapse, produce changes within neurons that signal to the nucleus and regulate the activity of numerous transcription factors and many other types of transcriptional regulatory proteins.3) A These nuclear changes gradually and progressively build with repeated drug exposure and underlie stable changes in the expression of specific target genes which, in turn, contribute to the lasting changes in neural function that maintain a state of addiction.1,4)

Bottom Line: Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state.Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction.As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype.

View Article: PubMed Central - PubMed

Affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Mount Sinai School of Medicine, New York, USA.

ABSTRACT
Regulation of gene expression is considered a plausible mechanism of drug addiction given the stability of behavioral abnormalities that define an addicted state. Numerous transcription factors, proteins that bind to regulatory regions of specific genes and thereby control levels of their expression, have been implicated in the addiction process over the past decade or two. Here we review the growing evidence for the role played by several prominent transcription factors, including a Fos family protein (ΔFosB), cAMP response element binding protein (CREB), and nuclear factor kappa B (NFκB), among several others, in drug addiction. As will be seen, each factor displays very different regulation by drugs of abuse within the brain's reward circuitry, and in turn mediates distinct aspects of the addiction phenotype. Current efforts are geared toward understanding the range of target genes through which these transcription factors produce their functional effects and the underlying molecular mechanisms involved. This work promises to reveal fundamentally new insight into the molecular basis of addiction, which will contribute to improved diagnostic tests and therapeutics for addictive disorders.

No MeSH data available.


Related in: MedlinePlus